Administration of dexmedetomidine has been reported to improve inflammatory response in animals. We explored the effects of administering dexmedetomidine on the levels of C-reactive protein (CRP) and procalcitonin, and thus on inflammation, in patients with sepsis enrolled in a randomized clinical trial.The DESIRE trial was a multicenter randomized clinical trial in which adult patients with sepsis were sedated with (DEX group) or without (non-DEX group) dexmedetomidine while on mechanical ventilators. As a prespecified sub-analysis, we compared CRP and procalcitonin levels during the first 14 days of treatment between the two groups. The 14-day mortality rate, albumin level, and the number of patients with disseminated intravascular coagulation (DIC) were also assessed. We used generalized linear models to estimate the differences in these outcomes between groups. We also used the Kaplan-Meier method to estimate the 14-day mortality rate and the log-rank test to assess between-group differences.P = 0.03); procalcitonin—range, 1.2–37.4 vs. 1.7–52.9 ng/mL (P = 0.04)]. Albumin levels were higher in the DEX group  than in the non-DEX group . The percentage of patients with DIC did not significantly differ between the groups . The 14-day mortality rates in the DEX and non-DEX groups were 13 and 21%, respectively (P = 0.16).Our study comprised 201 patients: 100 in the DEX group and 101 in the non-DEX group. CRP and procalcitonin levels were lower in the DEX vs. non-DEX group during the 14-day treatment period [CRP—range, 5.6–20.3 vs. 8.3–21.1 mg/dL (Sedation using dexmedetomidine reduced inflammation in patients with sepsis requiring mechanical ventilation.NCT01760967. Registered on 4 January 2013.ClinicalTrials.gov,  The inflammatory response has catastrophic consequences in patients with sepsis, including multiple organ failure and death . Leukocy2-adrenergic agonist widely used for sedation of patients during mechanical ventilation [Dexmedetomidine is a highly selective αtilation . Severaltilation –9. Admintilation , 8 and ITo investigate the effect of administering dexmedetomidine on sepsis-induced inflammation, we compared the outcomes of patients with sepsis who were treated with or without dexmedetomidine for 14 days as part of the DESIRE clinical trial .This analysis was prespecified in the study protocol for the DESIRE trial before patient enrollment began. The DESIRE trial was a multicenter, open-label, randomized clinical trial that compared the sedation strategies of administering dexmedetomidine (DEX group) versus not administering dexmedetomidine (non-DEX group) in terms of mortality and ventilator-free days during a 28-day period . The triPatients in the DEX and non-DEX groups received other sedatives as needed to achieve the sedation target and analgesics if necessary. In both groups, the targets of sedation depth were a Richmond Agitation-Sedation Scale score of 0  during the day and − 2 (lightly sedated) during the night . The treThe primary outcome in this analysis was inflammation as indicated by CRP and PCT levels. The secondary outcomes were 14-day mortality, albumin (ALB) level, and sepsis-associated coagulopathy. The ALB level served as a marker of vascular permeability . The dist tests or Wilcoxon rank sum tests for continuous variables and chi-square tests or Fisher’s exact tests for categorical variables.Primary and secondary outcomes were analyzed according to the intention-to-treat principle. Continuous variables were presented as means with standard deviations (SDs) or medians with interquartile ranges, and categorical variables were presented as numbers and percentages. To compare patient characteristics between the groups, we used We used a generalized linear model (the GENMOD procedure) to examine the effect of administering dexmedetomidine on CRP, PCT, ALB, and FDP levels, PLT counts, and PT ratios and to account for repeated measurements in the same patient. We used a generalized linear model (the GENMOD procedure with logit) to determine the effect of administering dexmedetomidine on the number of patients with three or more SIRS characteristics and/or DIC. The variables describing patient status were the dependent variables, and treatment allocation was the independent variable with a repeated variable of patient. The cumulative incidence of mortality over the 14-day treatment period was estimated via the Kaplan-Meier method, and differences between the groups were assessed using the log-rank test.P value < 0.05 was considered statistically significant.All statistical analyses were performed using JMP version 11.2.0 (SAS Institute Inc.), and SAS version 9.4 (SAS Institute Inc.) software. A two-sided Among the 201 patients in our study, 127 (63%) were men, and the mean age was 69 years  (Table P = 0.03). PCT levels were measured on days 1, 4, 8, and 14 and were highest on day 1 in both the DEX (37.4 ng/mL) and non-DEX (52.9 ng/mL) groups .CRP and PCT levels in the DEX and non-DEX groups during the 14-day observation period are shown in Fig. P = 0.01).The ALB levels in the DEX and non-DEX groups during the 14 days after randomization are shown in Fig. 9/L in the DEX group and 104–299 × 109/L in the non-DEX group; P = 0.72). FDP levels were also similar in both groups . The PT ratio was highest in both groups on day 2 but overall was lower in the DEX group  than in the non-DEX group . The percentage of patients with three or more SIRS characteristics did not differ significantly between the DEX vs. non-DEX group . The levels of the DIC-associated variables were similar in both groups with the exception of the PT ratio (Supplement Table P = 0.49).The levels of the coagulation biomarkers and the number of patients with three or more SIRS characteristics during the 14-day observation period are shown in the Supplement Table 2   died during the 14 days after randomization. The mortality rates in the DEX and non-DEX groups were 13% (13 patients) and 21% (21 patients), respectively  may have influenced some of the management protocols. However, CRP, PCT, and ALB levels, 14-day mortality rates, and sepsis-associated coagulopathy would not be affected by the judgments of physicians. Although preparations containing ALB can increase albumin levels, the physicians in charge followed the guidelines regarding such preparations when treating patients with sepsis-associated hypoalbuminemia [The administration of dexmedetomidine significantly improved CRP, PCT, and ALB levels in patients with sepsis requiring mechanical ventilation. Because the anti-inflammatory effects of administering dexmedetomidine were not associated with the reduction of mortality in patients with sepsis at 14 days, further studies with larger sample sizes or administering higher doses of dexmedetomidine are warranted.Additional file 1: Supplemental Methods. Table S1. Scoring system for DIC. Table S2. Changes in DIC and DIC-associated variables. Figure S1. Flow of Participants in the DESIRE trial.


To evaluate the accuracy of robotic CT-guided out-of-plane needle insertion in phantom and animal experiments.XY and YZ planes were performed, and the same insertions were manually performed freehand, as well as guided by a smartphone application (SmartPuncture). Angle errors were compared between the robotic and smartphone-guided manual insertions using Student’s t test. In the animal experiment, 6 robotic out-of-plane needle insertions toward targets of 1.0 mm in diameter placed in the kidneys and hip muscles of swine were performed, each with and without adjustment of needle orientation based on reconstructed CT images during insertion. Distance accuracy was calculated as the distance between the needle tip and the target center.A robotic system (Zerobot), developed at our institution, was used for needle insertion. In the phantom experiment, 12 robotic needle insertions into a phantom at various angles in the XY plane and 0.6°, 6.3°, and 0.6° in the YZ plane, respectively. Robotic insertions in the XY plane were significantly (p < 0.001) more accurate than smartphone-guided insertions. In the animal experiment, the overall mean distance accuracy of robotic insertions with and without adjustment of needle orientation was 2.5 mm and 5.0 mm, respectively.In the phantom experiment, the mean angle errors of the robotic, freehand manual, and smartphone-guided manual insertions were 0.4°, 7.0°, and 3.7° in the Robotic CT-guided out-of-plane needle insertions were more accurate than smartphone-guided manual insertions in the phantom and were also accurate in the in vivo procedure, particularly with adjustment during insertion.Out-of-plane needle insertions performed using our robot were more accurate than smartphone-guided manual insertions in the phantom experiment and were also accurate in the in vivo procedure.• In the phantom experiment, the mean angle errors of the robotic and smartphone-guided manual out-of-plane needle insertions were 0.4° and 3.7° in the XY plane (p < 0.001) and 0.6° and 0.6° in the YZ plane (p = 0.65), respectively.• In the animal experiment, the overall mean distance accuracies of the robotic out-of-plane needle insertions with and without adjustments of needle orientation during insertion were 2.5 mm and 5.0 mm, respectively.• The online version of this article (10.1007/s00330-019-06477-1) contains supplementary material, which is available to authorized users. Computed tomography (CT)-guided interventional procedures such as ablation and biopsy primarily comprise needle insertion into the lesion under CT guidance. Although needle insertion is generally performed in the axial CT plane , out-of-plane needle insertion is occasionally required to achieve an anatomically safer tract. For example, needle insertion into the hepatic dome of the liver and the renal upper pole along a craniocaudally oblique tract may avoid transthoracic insertion accompanied by risks of pneumothorax and hemothorax , 2. HoweWe have been developing a robotic system to enable CT-guided needle insertion –6. In ouThe animal experiment was approved by the institutional animal care and use committee of our institution. The design of the robotic system  used herein Fig.  has beenXY and YZ planes . A 17-gauge biopsy introducer needle (TASK Laboratory) with six combinations of angles  application . The endpoint was the angle errors in the es Table . For robThe needle angle was measured in maximum intensity projections in the two planes at a CT console by a blinded author (S.O. with a 3-year experience in CT-guided interventions). The angle error was calculated as the difference between the predetermined angle and the angle after insertion. Then, the angle errors were compared between the robotic and smartphone-guided manual insertions. Using angle errors, the three-dimensional deviations of the needle tip at a depth of 8 cm were estimated  was used for insertion in two female swine   in the phantom experiment. CT scanning  was performed to determine the starting point for insertion, the needle angles required, and the needle tract length. Subsequently, the needle was set with the angles and then its tip was moved to the starting point. Correct needle orientation was confirmed by CT scanning along with reconstructed three-dimensional CT images. The needle was then inserted till the whole tract length at once in the group without adjustment. In the group with adjustment, in contrast, the needle orientation was checked by CT scans at two time points Fig. . The neeDistance accuracy was evaluated on axial CT images of 0.5 mm thickness with 0.3-mm intervals using software  by an author (S.O.). First, whether the needle hit the target was evaluated on the reconstructed three-dimensional images. The distance accuracy was then determined by calculating the Euclidean distance between the target center and the needle tip, using the CT coordinates. Lateral and depth errors were further evaluated (Appendix XY and YZ planes) was hypothesized to be 0.3°. With an α value of 0.05 and a β value of 0.2, 12 insertions in each group were required.In the phantom experiment, the number of needle insertions was calculated to verify the superiority of the robotic insertion compared to smartphone-guided manual insertion with respect to the angle accuracy. The absolute value of the mean difference in the angle errors between the two groups was estimated to be 1.0°, with a standard deviation of 0.5° in both groups. The correlation coefficient between the two planes  using EZR software .Numerical variables were compared using a two-sided Student’s XY plane and 0.6° , 6.3° , and 0.6°  in the YZ plane, respectively. Robotic insertions were significantly (p < 0.001) more accurate than smartphone-guided manual insertions in the XY plane. Robotic insertions resulted in significantly (p < 0.001) smaller predicted needle tip deviations  than did smartphone-guided manual insertions  at the insertion depth of 8 cm. Robotic insertions were significantly (p < 0.001) faster  than smartphone-guided manual insertions .The results of the phantom experiment are summarized in Table p < 0.001) better than that without adjustment . The results of lateral and depth errors are shown in Supplementary Table p < 0.001) longer than that without adjustment , requiring the median of four CT scans and the median of two needle adjustments during insertion. The tube current-time product  and dose-length product  during insertion in the group with adjustments were significantly (p < 0.001 for both) larger than the tube current-time product  and dose-length product  during insertion in the group without adjustments.The results of the animal experiment are summarized in Table The present study was conducted to evaluate the accuracy of out-of-plane needle insertion using our robot; such an insertion is generally difficult to perform accurately by hand. The results showed that our robot achieved accurate out-of-plane needle insertions in the phantom and the animals, which may indicate more choices for selection of needle trajectories in clinical cases, possibly making the procedure safer and more effective. In particular, it is notable that junior staff and even residents may perform out-of-plane insertion with difficult trajectories using our robot.XY plane and < 4.1° in the YZ plane. The phantom experiment in the current study revealed that robotic out-of-plane needle insertion was significantly more accurate than smartphone-guided manual insertion. The advantages of the robot are that the needle angles required may be easily and accurately obtained by numerical inputs on the touch panel and the angles may be maintained during insertion.Smartphone applications to assist needle insertion such as SmartPuncture and OncoGuide  seem quite unique , 9. A phDespite accurate needle angles in the phantom, the distance accuracy of robotic insertions in animals was limited to some extent if the needle orientation was not adjusted during insertion. This was attributed mainly to movement of targets and needle deviation during insertion , 5. AlthOther than our robot, several devices and robots to assist out-of-plane needle insertion have been evaluated. An electromagnetically guided system (IMACTIS) displays the needle path in real time on two-dimensional CT images reconstructed from preprocedural CT data , 10. A pThere were some limitations to our study. The type of the needle used, locations for needle insertion in swine, and combinations of needle angles tested were limited. Further, techniques of breath hold with the ventilator employed in the animal experiments were different from those in conscious patients. Therefore, it remains to be confirmed whether similar results can be obtained with other needles and angles at other locations in conscious clinical cases; this is an area requiring future research.In conclusion, robotic CT-guided out-of-plane needle insertions were more accurate than smartphone-guided manual insertions in the phantom and were also quite accurate in the in vivo procedure, particularly with adjustment of needle orientation during insertion.ESM 1(DOCX 4739 kb)


The aim of this study was to investigate the Uromonitor-V2®’s performance in detecting NMIBC recurrence and compare it with urine cytology. From February 2018 to September 2019 patients were enrolled. All subjects underwent a standard-of-care (SOC) cystoscopy, either as part of their follow-up for NMIBC or for a nonmalignant urological pathology. Urine cytology was performed in NMIBC patients. Out of the 105 patients enrolled, 97 were eligible for the study. Twenty patients presented nonmalignant lesions, 29 had a history of NMIBC with disease recurrence, and 49 had a history of NMIBC without recurrence. In NMIBC, the Uromonitor-V2® displayed a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 93.1%, 85.4%, 79.4%, and 95.3%, respectively. Urine cytology was available for 52 patients, and the sensitivity, specificity, PPV, and NPV were 26.3%, 90.9%, 62.5%, and 68.2%, respectively. With its high NPV of 95.3%, the Uromonitor-V2® revealed promising properties for the follow-up of patients with NMIBC.The costly and burdensome nature of the current follow-up methods in non-muscle-invasive bladder cancer (NMIBC) drives the development of new methods that may alternate with regular cystoscopy and urine cytology. The Uromonitor-V2 Bladder cancer (BCa) is the tenth most common type of cancer worldwide with more than 500,000 newly diagnosed cases in 2018 ,4,5,6,7.The high rates of disease recurrence and the risk for disease progression determine that frequent follow-up regime is highly required. The current follow-up schedule of patients with a history of NMIBC consists of regular surveillance cystoscopies in combination with urine cytology. Follow-up through regular cystoscopies and cytology should be maintained years following diagnosis and can even span throughout life . These e®, U-monitor, Porto, Portugal) was presented. The test evaluates a subset of hotspot alterations in three different genes  using real-time qPCR. These targeted alterations include some of the most common genetic events in NMIBC. Oncogene-activating mutations in fibroblast growth factor receptor 3 (FGFR3) are one of the most relevant drivers of urothelial transformation. These mutations are reported in BCa with an overall frequency of ~35% [RAS genes are found in a lower percentage (13%) of BCa. This frequency should be taken into account when finding new solutions in NMIBC follow-up, in particular since KRAS and FGFR3 mutations are mutually exclusive events [TERT promoter (TERTp) mutations are reported with different frequencies in several cancers, but particularly in NMIBC are present in up to 80% across different stages/grades and are absent in inflammatory or urinary infections [TERTp’s transversal high frequencies across different stages and grades elects it as a high-value “all-round” biomarker to be used in clinical practice of NMIBC detection [In recent years, several biomarker-based tests with significantly higher NPV emerged. Although promising, these tests need to be validated in a clinical setting before implementation . Recentl of ~35% ,13 and a of ~35% ,16,17,18e events . TERT prfections ,21,22,23etection ,25.There is currently a gap in the literature regarding the true prevalence of these alterations in NMIBC recurrences and the sensitivity in the detection of recurrent lesions when screened in combination. Since these alterations present, at this time, some of the most common genetic events in NMIBC tumors, it became imperative to elucidate their potential to detect NMIBC recurrence in urine. In a previous multicenter study on NMIBC patients, in follow-up the test showed promising results with a sensitivity, specificity, and NPV of respectively 100%, 83.8%, and 100% in a subgroup of 24 NMIBC recurrent patients . With th® detection, whereas the remaining two samples did not have sufficient material for testing. Of the 97 eligible patients, 77 presented a history of NMIBC. Of these, 29 were positive for recurrence during enrollment cystoscopy. An overview of the clinicopathological information of the eligible patients is presented in p = 0.004).From the 105 enrolled subjects, eight were deemed ineligible for inclusion, leading to 97 patients being eligible for inclusion in the study. Five of the ineligible patients were previously diagnosed with a muscle-invasive tumor; one failed Uromonitor-V2®, 36 (37.1%) patients presented a positive result, while the remaining 61 (62.9%) were negative. Of the 97 patients, 29 subjects were positive for disease recurrence at time of enrollment. The Uromonitor-V2® was able to identify 27 of the recurrent samples; two samples were undetected. Histological material from transurethral resection of the bladder tumor (TURBT), or biopsy of the tumor was available in fourteen of the recurrence-positive patients. Of the pathologically proven recurrences, six were diagnosed with a Ta tumor, two with a T1 tumor, five patients with CIS, and one patient progressed to a muscle-invasive tumor. All fourteen of the histologically proven patients had a positive result in the Uromonitor-V2® test. The fifteen recurrences without histological evidence were clinically diagnosed as low-grade Ta tumors by the attending urologist based on tumor history and tumor appearance.Out of the 97 patients who were successfully tested with Uromonitor-V2®-positive, of which 27 were recurrence-positive. For the remaining positive samples, seven were of patients with a history of NMIBC without a detectable recurrence, while two were of patients without a history of bladder cancer. Follow-up data were available for six of the Uromonitor-V2® false-positive NMIBC patients. At six months follow-up, five patients had no sign of disease recurrence and one patient was suspected for CIS. No pathological confirmation for the suspected CIS was obtained due to the patient’s poor clinical condition. In the two benign patients with a positive Uromonitor-V2® result, one patient underwent a cystoscopy for lower urinary tract symptoms due to benign prostate hyperplasia, while the other patient presented with urge incontinence.In total, 36 samples were Uromonitor-V2® presented an overall sensitivity of 93.1% (27/29), a specificity of 86.8% (59/68), a positive predictive value (PPV) of 75.0% (27/36), and an NPV of 96.7% (59/61). In The Uromonitor-V2®. In this study, urine cytology showed a sensitivity, a specificity, a PPV, and an NPV of 26.3%, 90.9%, 62.5%, and 68.2%, respectively. An overview of the Uromonitor-V2® test characteristics in comparison with cytology is presented in Results of cytology, collected at enrollment cystoscopy, were available for 52 samples. Nineteen were from patients with recurrent disease, of which five had a positive cytology (TPS4/TPS5); one cytology result was equivocal (TPS3); while the remaining were negative (TPS2). All patients who had positive cytologies were positive for the Uromonitor-V2®. The current pitfalls of the follow-up methods in BCa result in a high economic burden with BCa being accountable for 3% of all cancer costs within the European Union [® to monitor recurrence in patients with NMIBC revealed a sensitivity, specificity, PPV, and NPV of 93.1%, 85.4%, 79.4%, and 95.3%, respectively. The latter contrasts with urine cytology results and, available for 52 patients, displayed a decrease in sensitivity, specificity, PPV, and NPV . Over the last decades, multiple biomarker-based urine assays were developed to act as an additive to the current follow-up methods, or even as a  replacement. Tests such as the NMP22, BTA stat, or UroVysion were FDA-approved, but none of them is widely used routine as no relevant NPV is achieved [®, an NPV of 95.3% was achieved, demonstrating a high performance in screening the cohort of NMIBC patients. The use of well-established technologies and affordable equipment leads to clear advantages in the implementable of Uromonitor-V2® capacity in different centers and reduced test costs; the entire procedure relies on affordable and easy-to-use components. It is based on the use of real-time qPCR, a methodology that is well implemented in most laboratories, allowing in-house testing. Another clear advantage of the test is the short six-hour period response that creates a binary response, a yes-or-no result. While only being tested in a restricted number of samples, the presence of nonmalignant urological pathologies did not interfere with the Uromonitor-V2® test performance. As a drawback of this study, it is necessary to point out the relatively low number of histologically confirmed recurrences. Histological confirmation was available in fourteen of the 29 patients. Whether a patient with disease recurrence was referred for tumor removal was a decision based on the visual appearance of the tumor and prior tumor history. All the resected bladder tumors were detected by the Uromonitor-V2®. Only two tumors detected through cystoscopy and/or cytology, but not confirmed by histology, were unidentified by the Uromonitor-V2®; they corresponded to patients previously diagnosed with pTa, low-grade tumors, and in both, the tumors were relatively small (max. diameter 5 mm and 12 mm). These tumors might represent false-positive cystoscopy or cytology results, however without histological confirmation this cannot be demonstrated. Still, missing these small, low-grade tumors could be considered a defendable act since they do not determine the course of the disease, and can be followed in an active surveillance strategy. No sub-analysis on high-grade recurrences was conducted due to the relatively low number of pathologically confirmed recurrences. It would be interesting to test the Uromonitor-V2® in a larger cohort of high-grade NMIBC patients in a future research study. This study would also benefit from longer-term follow-up data, especially in NMIBC patients who presented a positive Uromonitor-V2® test but were considered recurrence-negative, according to current follow-up methods. These false-positive patients are of extreme interest since they might harbor microscopically recurrences that are not detected by the current combination of cystoscopy and cytology, and the Uromonitor-V2® would be an invaluable tool in this screening setting.The high number of cases with disease recurrence in NMIBC patients can be partially explained by inadequacies of the current follow-up methods. While white light cystoscopy (WLC) is an adequate method for detecting papillary lesions, it lacks adequacy in the detection of, for example, CIS or microscopic lesions . Methodsan Union . These rachieved . Some ofachieved ,32,33. F® test results. All were enrolled prior to undergoing a cystoscopy at the hospital’s outpatient clinic. Three groups of patients were subsequently identified: (1) patients with a history of NMIBC with a recurrence at time of cystoscopy; (2) patients with a history of NMIBC without a recurrence at cystoscopy; and (3) patients without a history of BCa, undergoing cystoscopy for benign urological causes. Patients were eligible for inclusion if they were ≥18 years of age, able to give written consent and provide a minimum of 10 mL of urine prior to undergoing standard-of-care (SOC) cystoscopy. NMIBC patients in follow-up could be enrolled if they had an event  within five years prior to enrollment. Exclusion criteria were inadequate material for testing; a failed Uromonitor-V2® test; previous diagnosis with muscle invasive bladder; or, in case of the benign control group, any prior history of bladder cancer.This was a prospective, blinded, single-visit, case-enriched cohort study. All patients in this study were under follow-up at the Radboud University Medical Center in Nijmegen, the Netherlands, either because of a history of NMIBC or because of a benign, non-BCa related urological pathology. Next to enrolling patients with a history of NMIBC, a subgroup of non-BCa patients were enrolled to test whether the presence of nonmalignant urological pathologies would interfere with the Uromonitor-V2Clinical information of all patients was collected. Informed consent was obtained from all patients. All procedures described in this study were in accordance with national and institutional ethical standards and the Declaration of Helsinki, and the trial was approved (19 December 2017) by the local ethics committee.All urine collections were carried out within the standard clinical surveillance program of the participating patients, in which all patients came in for a regular follow-up cystoscopy and were asked to provide additional urine in parallel. Additional cytology was collected for those patients with a history of NMIBC. Following urine collection, all patients underwent an SOC cystoscopy by a urologist or a urologist in training who inspected the bladder for any abnormalities. Recurrence was defined as either pathologically proven disease following TURBT or was the clinical decision of the attending urologist.® Filter-Z612545, Merck, Darmstadt, Germany) containing a house-made conservative storage buffer [® Plasma/Serum Cell-Free Circulating DNA Purification Mini Kit  as described [TERT, FGFR3, and KRAS testing was performed on 25–50 ng of the extracted DNA. The extracted DNA was amplified and detected on a qPCR real-time machine  using the proprietary chemistry for amplification and detection, as provided in the Uromonitor-V2® test kit. Amplification signals were analyzed as recommended by the manufacturer . If at least one of the screened alterations provided a positive result, then the test was positive. Refer to After collection, the urine was filtered using a pretreated 0.80 µm nitrocellulose syringe filter . Descriptive statistics were performed and differences between groups were tested by the Student’s ® as a promising test with characteristics for detecting recurrence in NMIBC patients under follow-up. The test displayed its potential as an alternative to the current follow-up methods, in the current validation study and in the previous study on the Uromonitor-V2®, with comparable findings [® could serve as a  replacement for cystoscopy and/or cytology.With a sensitivity of 93.1%, specificity of 85.4%, and an NPV of 95.3% this study presents Uromonitor-V2findings . Further


The results showed that the Ag-NPs were uniformly dispersed in solution, and the solution had strong antibacterial activities. It was found that the one-pot synthesis allowed the growth of and cross-linking with cellulose processes of Ag-NPs conducted simultaneously. Approximately 61% of Ag-NPs was successfully loaded in CANF, and Ag-NPs were uniformly dispersed in the surface and internal of the composite film. The composite film exhibited good tensile properties (tensile strength could reach up to 86.4 MPa), transparency (light transmittance exceeds 70%), thermal stability, and remarkable antibacterial activities. The sterilization effect of CANF0.04 against Staphylococcus aureus and Escherichia coli exceed 99.9%. Due to low residual LiCl/DMAc and low diffusion of Ag-NPs, the composite film may have potential for applications in food packaging and bacterial barrier.Using N,N-dimethylacetamide (DMAc) as a reducing agent in the presence of PVP-K30, the stable silver nanoparticles (Ag-NPs) solution was prepared by a convenient method for the in situ reduction of silver nitrate. The cellulose–Ag-NPs composite film (CANF) was cast in the same container using lithium chloride (LiCl) giving the Ag-NPs-PVP/DMAc solution cellulose solubility as well as  Silver nanoparticles (Ag-NPs) refer to silver clusters with a particle size of 1 to 100 nm, which possess a large specific surface area and have a good inhibitory effect against Gram-positive bacteria, Gram-negative bacteria, fungi, Pseudomonas, and bacteriophages ,3,4. Cur+. When Ag+ was fully immersed into the film, the reducing agent was used to reduce the Ag+ and precipitate to obtain silver loaded composite films. reducing agents, such as glucose and sodium borohydride, are widely used [Cellulose molecules have active hydroxyl groups that can be combined with other polymers, inorganics, organics, and nanomaterials. It expresses the characteristics of environmentally friendly, cheap, easy to obtain, and facile film formation abilities . To makeely used ,27,28. Tely used . Howeverely used .+ with in situ generation in N,N-dimethylacetamide (DMAc) under the protection of polyvinylpyrrolidone (PVP) for short time to form a small size of Ag-NPs/PVP solution. Cellulose was dissolved in the solution as Ag-NPs continue to grow, aiming to enhance the dispersibility of Ag-NPs within cellulose and the solution. And the mixture was further cast to silver loaded cellulose composite film. Only one reagent (DMAc) was used in the experiment, and all reactions can be completed in a single container, which reduces the cost of the reagents and without complex operation. The morphology and chemical structure of the Ag-NPs were characterized by Fourier transform spectroscopy (FT-IR), X-ray diffraction (XRD), and transmission electron microscope (TEM). The surface morphology and chemical structure of the composite film were evaluated by scanning electron microscopy (SEM), thermogravimetric analysis (TGA), X-ray photoelectron spectroscopy (XPS), XRD, gas chromatography–mass spectrometer (GC-MS), inductive coupled plasma emission spectrometer (ICP), light transmittance and haze detection, and tensile tests. The minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) value, inhibition zone, and contact antibacterial ability of the fabricated films against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) were investigated to provide further research with theoretical supports.To solve this problem, we put forward a pre-reaction that reduces Agα-cellulose >80%) was experimentally self-made via the preparation method described in previous experiments [γ-Mercaptopropyltrimethoxysilane (MPTS) was provided by Macklin Biochemical Technology Co., Ltd. . Silver nitrate solid was purchased from Haiyinpeng Chemical Trade Co., Ltd. . Polyvinylpyrrolidone-K30 (PVP), lithium chloride (LiCl), N,N-dimethylacetamide , and other analytical reagents used in the experiment were purchased from Fuyu Fine Chemicals Co., Ltd. . S. aureus (ATCC 6538) and E. coli (ATCC 25922) were obtained from China General Microbiological Culture Collection Center .Cellulose  into a 150 mL flat bottom flask. Then, we added 0.3 g of PVP and 45 g of DMAc to the flask and shook thoroughly until the solution turned brown. The solutions were placed in the dark room at 40 °C for 1 h and 4 h, respectively, to obtain organic Ag-NPs solution with different reaction degrees. We weighed 0.3 g of PVP and 45 g of DMAc to a flask as a blank control solution. Solutions were used to characterize the morphology, chemical structure, and antibacterial activity of Ag-NPs.First, we weighed 0.0630 g of AgNO3  into a 150 ml flat-bottom flask. We added 0.3 g of PVP and 45 g of DMAc to the flask and shook thoroughly until the solution turned brown. The solution was placed in the dark room at 40 °C for 1 h, to obtain organic Ag-NPs solutions with different silver contents. The solution was used for further film fabrication. We eeighed 0 g, 0.0079 g, 0.0158 g, 0.0315 g, 0.0630 g, and 0.1260 g of AgNO+(DMAc)Cl- structure providing the Ag-NPs solution with cellulose solubility. The major function of this system is to break the most hydrogen bonds of cellulose structures and thereby disperse cellulose in solution [0.005, CANF0.01, CANF0.02, CANF0.04, and CANF0.08, respectively. We took out the solutions with different silver contents, added 50 μL of MPTS, and stirred in a 50 °C oil bath for 4 h to prepare the coupled Ag-NPs solutions. We accurately weighed 4 g of LiCl solids into the solution and stirred at 105 °C until the solids were dissolved. LiCl was added to form a 8% LiCl/DMAc system. Note that LiCl/DMAc as a widely used cellulose solubilizing system, and LiCl associated with DMAc to form a special Lisolution . One graThe micromorphology and size of the Ag-NPs were observed via TEM  at acceleration voltage of 80 kV. The droplets of Ag-NPs solution at reaction time of 1 h and 4 h were dropped on the carbon-coated electron microscopy grids and measured directly. The sizes of Ag-NPs were measured from the TEM images using a Nano Measurer software. −1 to 4000 cm−1 with a resolution of 4 cm−1. The samples were pretreated by quick vacuum drying at 20 °C to form the thick films, following by total reflection scanning. The FT-IR spectra of reacted 4 h of Ag-NPs solution and PVP blank solution were collected on a Frontier instrument  in the range from 400 cmθ = 5° to 80° at a scanning rate of 4°/min. The relative average particle size (D) of samples was estimated using the Scherrer formula, as shown in Equation (1):D is the average thickness of the crystal grains perpendicular to the crystal plane, which is used as the average particle size of Ag-NPs; K is the Scherrer constant with a value of 0.89; B is the full width at half maximum (FWHM) of the diffraction peak; θ is the Bragg diffraction angle; and γ is X-ray wavelength with a value of 0.154056.An XRD  with Ni-filtered Cu Kα radiation was utilized at an operating voltage of 40 kV and current of 30 mA to analyze the crystal structure of Ag-NPs and PVP thick film samples. The diffraction intensities were collected between 20.04 were observed via SEM  at low acceleration voltages of 12.5 kV. The films were coated with gold by a vacuum sputter coater  before observation. XRD was used to measure and calculate the average particle size of Ag-NPs and cellulose crystallinity in the films. The cellulose crystallinity was calculated by the ratio of the crystalline area to the amorphous area of the samples.The surface and cross-section micromorphology of RCF and CANF0.04 surface was measured using XPS scanning . The scanning method performed full scan of the samples (resolution: 1 eV), and accurately scan the C1s and Ag3d peak areas of the samples (resolution: 0.1 eV). The C, O, and Ag content of the RCF and CANF0.04 were studied by GC/MS  with Agilent 19091S-433 column and EI ion source. The test method was according to the SN standard SN / T 3587-2016. The safe residual dose of DMAc was based on OEKO-TEX certification Standard100. A 100 μg/mL DMAc standard solution was used as the threshold to determine whether the solvent content exceeded the standard. The Li residuals in RCF and CANF0.04 films were studied by ICP . One gram of RCF and CANF0.04 were digest it in 20 mL of 72% concentrated sulfuric acid, respectively. Added 20 mL of 64% nitric acid until the solution becomes clear, and set volume to 1 L with deionized water for measuring.The main residuals in the film samples obtained from the experiments were DMAc and Li element. The DMAC residues in RCF and CANFAccording to the ISO 1924-2 (2008) standard, mechanical property tests were conducted at room temperature using a universal testing machine . The cross-head speed was 10 mm/min. The dimensions of the test films were 100 mm × 10 mm × 0.02 mm to 0.04 mm. The initial separation of the grips was 50 mm.0.04 were measured using a light transmittance/haze meter . The light source was a standard light source C, and the films selected for testing were thickness of 0.03 mm. The light transmittance and haze of the RCF and CANF0.04 was measured by TGA using a TG analyzer  at a heating rate of 20 °C/min from 50 °C to 750 °C under a high purity air atmosphere. The thermal stability of RCF and CANFE. coli and S. aureus was determined by MIC and MBC values. Both MIC and MBC were measured according to the Clinical and Laboratory Standards Institute standards CLSI M07-A10 (2015) and CLSI M26-A (1999). The antibacterial activity of Ag-NPs against 6 CFU/mL fresh bacterial bacteria solution was evenly coated on the nutrient agar (NA) plate in the clean bench. Then, 13 mm diameter of round punched RCF to CANF0.08 was attached to the surface of the plate. The plates were incubated at 37 °C for 48 h, and the inhibition zone diameter of the films was simply measured with a vernier caliper.The antibacterial activity of composite films against two kinds of bacteria was qualitatively tested by the film inhibition zone; 0.5 mL of 106 CFU/mL of fresh bacterial bacteria solution was coated on the surface of the blank plate (RCF and CANF0.04), and covered with polypropylene films. After incubation at 37 °C for 24 h, the plate, film, and cover film were washed carefully using 20 mL nutrient broth (NB)/H2O eluent with a volume ratio of 1:100 (v/v); 0.5 mL of the eluate was then coated on the NA plate and incubated for 48 h at 37 °C with a humidity of >95% before the growth of bacteria was observed.The contact sterilization ability of silver loaded cellulose films against the two types of bacteria was determined according to the ISO 22196 (2011) standard. Approximately 10+ continues to be reduced in situ in existing nanoparticles, deepen the austenitic maturity of Ag-NPs [+ was reduced to Ag-NPs. When PVP formed a coating on the surface of Ag-NPs, the agglomeration process effectively reduced, thus the size of the silver nanoparticles was stabilized within a certain range and closer to the normal distribution. DMAc possess low ionization energy and electron affinity, which has a weak ability to reduce silver ions, resulting in low rate of silver nanoparticles form to crystal nuclei, and thus the small size Ag-NPs can be prepared . After of Ag-NPs , thereby−1 and the stretching vibration peaks of –CH at approximately 2950 cm−1 in both lines. The C=O stretching vibration peaks at PVP spectrum was 1655 cm−1, whereas the peak of silver was slightly blue shift in Ag-NPs/PVP, which is similar to that described in related literature [−1  silver plane (111), (200), and (220), respectively. The average crystal size of Ag-NPs estimated by Scherrer formula was 14.88 nm, which was consistent with the actual silver nanoparticles size range (13–28 nm) observed by TEM. The analysis results show that the small size Ag-NPs protected by PVP exist stably in DMAc solution.The XRD patterns  showed 20.04 compared with RCF  of MPTS could completely coat the nanoparticles, and most of them may be removed during the immersion process. The oxygen and carbon atomic ratios (O/C) of RCF and CANF0.04 surface were 0.522 and 0.558, respectively, which were close to the O/C values of common wood fibers [0.04, which indicated that the addition of Ag-NPs may introduce some oxygen-rich components on the film surface. The C1 , C2 , and C3  content obtained from C1s spectrum of RCF were close to the CANF0.04 . Therefore, the immersing process could effectively remove the most residual Li/DMAc system of the film, reducing potential harm to organic beings. The lithium element content of RCF and CANF results  showed t0.04 were dense , and the elongation at break increased more than 50% . The val0.04 showed two rapidly weight loss stages (0.04 was probably due to the water release of cellulose films. RCF and CANF0.04 were in hydrogel form, more bound water remained in the structure, and a large amount of bound water evaporated in this stage which may cause a rapid weight loss. Differences in weight loss for RC and CANF0.04 in this range may due to the swelling ability which could decrease because of Ag-NPs [0.04 was smaller than RCF, which reflected the coupling Ag-NPs could improve the thermal stability of cellulose film. When the temperature reached to 750 °C, the residual weight of RCF was 0.32%, and the CANF0.04 was 2.77%. It can be determined that the main component of the extra residue was silver, which was stable at high temperature [0.04 and the weight of silver added in CANF0.04, the weight ratio of the Ag-NPs successfully loaded in CANF0.04 was ~61%, indicating that most of the silver was utilized, which was in line with the “sustainable” concept advocated by current research.The TG and DTG curves of RCF and CANFs stages a,b. At 1f Ag-NPs . The weiperature . Based o600 values, the MIC values against E. coli and S. aureus were 32 μg/mL and 64 μg/mL, respectively, revealing that the solution has been able to inhibit bacterial growth and reproduction at lower concentrations. Studies have shown that the bactericidal mechanism of Ag-NPs is mainly caused by silver clustering and anchoring to the negatively charged sites of bacterial cell wall, and then destroying the cell wall to kill bacteria [S. aureus with thicker cell wall to antibacterial agents is higher than that of Gram-negative E. coli with thinner cell wall [E. coli was slightly stronger than S. aureus, and the MIC values of S. aureus were higher than E. coli. Based on the MBC test result, the bactericidal ratio of E. coli was more than 95% when the Ag-NPs concentration increased to 64 μg/mL, indicating that 64 μg/mL was the MBC value of Ag-NPs against E. coli, and the MBC value of Ag-NPs against S. aureus was 128 μg/mL can be determined as well. Lower MIC and MBC values suggest that a small amount of silver Ag-NPs could make the film antibacterial.The Ag-NPs solution showed strong antibacterial properties. Based on the difference in ODbacteria . Howeverell wall . Therefo0.02, CANF0.04, and CANF0.08 have obvious circles against both bacteria. The increase of Ag-NPs concentration enlarged the Inhibition Zone of films, suggesting that the antibacterial activity of films is determined by the concentration of Ag-NPs. The inhibitory zone diameter of CANF0.04 and CANF0.08 against E. coli was greater than 5 mm, and the diameter against S. aureus was greater than 3 mm. This indicated that the Ag-NPs in composite films owned antibacterial diffusivity when the concentration reached to a certain degree. Studies have shown that Ag-NPs has cytotoxicity in vitro experiments. When the concentration was exceeded 1 mg/kg, experimental mice exhibited liver toxicity via taken orally [0.04 diffused in NA plate was 35.3 μg, which was lower than the dose that produced cytotoxicity. The results suggest that the diffusivity of Ag-NPs may be less harmful to the organism, and cytotoxicity need to be further characterized. Thus, the composite films may have the potential to be applied in some biological fields.The results of the inhibition zone test  showed tn orally . The ICP0.04 did not multiply. It can be seen that the contact sterilization effect of CANF0.04 against both bacteria exceed 99.9%. The remarkable bactericidal effect can be attributed to the large number of Ag-NPs uniformly distributed on the surface of the CANF0.04 (Two kinds of bacteria incubated on the blank NA plate and RCF NA plate grew well , whereasCANF0.04 b, which 0.04 makes it easier for the Ag-NPs attached to the bacterial cell wall and kill the bacteria that gives the film good antibacterial properties. In addition, the amount of residual LiCl/DMAc system in the film was low, and the amount of silver diffusion was lower than the dose that produces cytotoxicity. Therefore, the silver-loaded cellulose film obtained in the experiment may have potential for applications in food packaging and bacterial barrier.In summary, this study investigated the preparation of Ag-NPs solution using in situ reduction and one-pot synthesis of cellulose-Ag-NPs composite films. Due to the aggregation effect of Ag-NPs and the coupling effect of MPTS, the process of Ag-NPs growth and cross-linking with cellulose during the one-pot synthesis were conducted simultaneously. A uniform Cellulose-Ag-NPs composite film was successfully prepared. The CANF have better tensile properties, thermal stability, and antibacterial ability because of Ag-NPs. The large number of Ag-NPs uniformly distributed on the surface of the CANF


Neoadjuvant endocrine therapy (NET) has demonstrated efficacy in post-menopausal patients with hormone-responsive breast cancer. This trial was designed to compare the efficacy of neoadjuvant chemotherapy (NCT) with NET in pre-menopausal breast cancer.In this prospective, randomised, phase III study, oestrogen receptor (ER)-positive, HER2-negative, and lymph node-positive pre-menopausal breast cancer patients were recruited from 7 hospitals in South Korea. Enrolled patients were randomly assigned (1:1) to receive 24 weeks of either NCT or NET with goserelin and tamoxifen. The primary purpose was to evaluate the non-inferiority of NET compared to NCT using clinical response, assessed by MRI. Besides, pathological complete response rate (pCR), changes in Ki-67 expression, breast conservation surgery (BCS) rate, and quality of life were included as secondary endpoints.n = 95) or NET (n = 92), and 87 patients in each group completed treatments. More NCT patients had complete response or partial response than NET patients using MRI  and callipers . Three NCT patients (3.4%) and one NET patient (1.2%) showed pCR (p < 0.005). No difference existed in the conversion rate of BCS  and Ki-67 change (p = 0.114) between the two groups. Nineteen NCT patients had treatment-related grade 3 or worse events compared with none in the NET group.A total of 187 patients were assigned to receive NCT (Better clinical responses were observed in pre-menopausal patients after 24 weeks of NCT compared to those observed after NET.Clinicaltrials.gov, NCT01622361. Registration June 19, 2012. For hormone-responsive breast cancer, the question of which patients can safely be spared adjuvant chemotherapy has been extensively studied. For cases involving hormone receptor-positive tumours, younger patients (< 35 years old) show a poorer prognosis than older patients in terms of tamoxifen resistance . HoweverTreatment decisions based on demographic characteristics and tumour burden have the potential to overtreat many individuals and undertreat others. The Oncotype DX assay has been studied for lymph node-positive breast cancer patients, and the SWOG 8818 study reported that the low-risk Oncotype DX group gained no additional benefits from chemotherapy . SOFT anNeoadjuvant treatment has benefits, which include reducing the tumour burden and evaluating the treatment response of the tumour. The response to neoadjuvant chemotherapy (NCT) is diverse and varies according to the intrinsic subtype. ER-positive, HER2-negative breast cancer shows a reduced pathologically complete response (pCR) rate, but better survival than other subtypes. Moreover, pCR is not related to survival in the luminal A subtype . TherefoTherefore, we hypothesised the non-inferior response of NET compared with NCT and reported a phase III clinical trial to compare the response between NCT and NET in pre-menopausal women with ER-positive, HER2-negative, and lymph node-positive breast cancer.ClinicalTrials.gov as number NCT01622361.This is a phase III, open-label, prospective, randomised, multicentre, neoadjuvant study of chemotherapy versus endocrine therapy in pre-menopausal patient with hormone-responsive, HER2-negative, lymph node-positive breast cancer [NEST]. Seven centres belonging to the Korean Breast Cancer Society Group (KBCSG-012) participated in this study. The study protocol has been approved by the Korea Food and Drug Administration (KFDA), as well as the institutional review board of every trial centre, and was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and the applicable local regulatory requirements on bioethics. For safety issue, the response rate of both groups was planned to be monitored. An independent data monitoring committee (IDMC) was established to monitor the study progress. The IDMC was responsible for deciding whether to continue the study when 66 patients in each treatment group completed their treatment regimens. This trial has been registered in Eligible patients included pre-menopausal women with histologically confirmed ER-positive, HER2-negative, and lymph node-positive primary breast cancer. Lymph node positivity was required to be proven histologically prior to the start of treatment with core needle biopsy or fine needle aspiration. All patients were aged between 20 and 50 years. Pre-menopausal status was defined based on the following: (1) last menses within 6 months of randomisation and (2) for patients who have had hysterectomy, E2 ≥ 20 pg/ml and FSH < 30 mIU/ml within 4 weeks of randomisation. ER positivity was defined as Allred score ≥ 3 or modified Allred score ≥ 4. Patients with inflammatory breast cancer, bilateral breast cancer, evidence of distant metastasis, or other malignancy were excluded. Written informed consent was obtained from all participants.Patients were enrolled by the study investigators. Patients were randomly assigned (1:1) to receive either NCT or NET for 24 weeks prior to surgery. Block randomisation was performed using the e-CRF system, with patients stratified by the treating centre and clinical stage (stages II and III). Patients who signed an informed consent form entered screening and were assigned a unique patient screening number. Patients who completed the screening process and met all eligibility criteria were randomised through a central randomisation website. No patients were enrolled or began treatment prior to randomisation, and the assignment of a randomisation number was undertaken using the website. Adverse events were recorded at every patient visit and assessed according to the Common Terminology Criteria for Adverse Events Version 3.0.2 adriamycin plus 600 mg/m2 cyclophosphamide intravenously) every 3 weeks for 4 cycles, followed by taxol (75 mg/m2 docetaxel intravenously) every 3 weeks for 4 cycles, or goserelin acetate 3.6 mg every 4 weeks with tamoxifen 20 mg daily. Treatment continued for 24 weeks before surgery  to receive either adriamycin and cyclophosphamide (60 mg/m:1 to recAll patients underwent breast magnetic resonance imaging (MRI) before the start of treatment and after the end of treatment before surgery. Additionally, during treatments , calliper measurement of the tumour size was performed. We determined the objective tumour response with every measurement method and assessed the response according to the modified RECIST . SurgeryAll immunohistochemical analyses of ER and Ki-67 expression were performed and reviewed at the central laboratory . Ki-67 was stained with an antibody for MIB-1 for assessment, using a sample of the core biopsy prior to treatment and a surgery specimen after treatment. The Ki-67 index was calculated as the percentage ratio of Ki-67-positive cells to total cells.The primary endpoint was the clinical response rate at 24 weeks, as determined using calliper and MRI measurements. We performed tumour measurements using callipers every 3 weeks for the NEC group and every 4 weeks for the NCT group, and MRI at day 0 and week 24. A clinical response included either a complete response (CR) or a partial response (PR) according to the Response Evaluation Criteria In Solid Tumour (RECIST) version 1.1 criteria. Secondary endpoints were the rate of pCR, the rate of breast conservation surgery, Ki-67 changes, the length of time to maximum response within a treatment period, and QoL, using the European Organisation for Research and Treatment of Cancer Quality of Life (EORTC QOL BR23) questionnaire. Adverse events were recorded at every patient visit and assessed according to the Common Terminology Criteria for Adverse Events Version 3.0.The sample size was calculated based on the clinical response rate measured by MRI in each group, the NCT and NET groups, under the assumption that the effect of NET would be non-inferior to that of NCT. Sample sizes of 131 in each group achieve 80.055% power to detect a non-inferiority margin difference between the group proportions of − 0.1500  for the difference in response rates between groups being 15% or less), when the MRI response rate of NCT and NET was estimated to be approximately 75%. A total of 290 patients were required .t test for mean differences and chi-squared test for frequencies were used. A 2-sided p < 0.05 was considered statistically significant. All analyses were conducted using SAS version 9.4  and R version 3.6.1.Because of enrolment failure, a total of 194 patients were enrolled until September 24, 2014. All data analysis was performed according to a pre-established analysis plan. A two-sided 95% confidence interval for the difference in the incidence of morbidity was calculated to test for non-inferiority. As a non-inferiority design had been adopted, difference of the response rate between group and the 95% CI was calculated, using the index of NCT as the reference. NET would be considered to be non-inferior to NCT when the lower limit of the CI is greater than − 0.15. Because of enrolment failure, a total of 194 patients were enrolled until September 24, 2014. To draw a comparison between the two groups, AstraZeneca participated in the funding of the study. The authors had complete access to the study data, and the corresponding author had the final responsibility for publication submission.p = 0.891). Forty-eight percent of NCT patients and 61% of NET patients were expected to undergo mastectomy prior to the start of treatment (p = 0.142).A total of 187 patients from 7 participating centres were included and randomised. Seven patients in the NCT group and 5 patients in the NET group withdraw their consent. One patient in the NCT group was randomised but did not receive treatment. Therefore, a total 174 patients completed the scheduled treatment and were finally analysed . The clinical response rate measured using MRI was 83.7% (72 of 87 patients) with NCT and 52.9% (45 of 87 patients) with NET . On callipers, the clinical response rate was 83.9% (73 of 87 patients) with NCT and 71.3% (62 of 87 patients) with NET  (Table Tumour size decreased over 24 weeks in both treatment groups (p = 0.531). Three NCT patients (3.4%) and one NET patient (1.2%) showed pCR (ypT0ypN0M0) (p < 0.005). Twelve NCT patients (13.8%) and 4 NET patients (4.9%) had complete lymph node response (p < 0.005). However, Ki-67 expression change during the treatment period was not significantly different between the two groups .The conversion rate of breast-conserving surgery (BCS) with neoadjuvant treatment in patients who planned to have total mastectomy was 13.8% in the NCT group and 11.5% in the NET group, which was not significantly different (Nineteen NCT patients (21.8%) had treatment-related grade 3 or worse adverse events, with no adverse effects in the NET group.Exploratory subgroup analysis was performed. There was a difference of tumour response according to Ki-67 expression. For patients with a low Ki-67 expression ≤ 20%), the clinical response rate was 83.7% (41/49) in NCT, 60.4% (29/48) in NET with MRI, and 69.4% (34/49) in NCT, 83.3% (40/48) in NET with calliper. Among the high Ki-67 expression group (> 20%), the response rate was 81.1% (29/36) in NCT, 40.5% (15/37) in NET by MRI, and 77.8% (28 /36) in NCT, 78.4% (29/37) in NET by calliper . Neoadjuvant therapy was comparatively more effective in patients with low Ki67  while chemotherapy was equally effective irrespectively of Ki67 .This study is the first to compare NCT with NET (tamoxifen plus ovarian function suppression) in pre-menopausal breast cancer only. This study is also unique because the patients were all ER-positive/HER2-negative and lymph node-positive.The primary finding of this study was that the response to NET was inferior to NCT in pre-menopausal ER-positive/HER2-negative subtype breast cancer. The pCR rate was also higher in the NCT group than in the NET group. However, this does not imply that NCT patients will have a better long-term survival outcome than NET patients. First, the changes in Ki-67 expression were not different between the two groups. In addition, NET patients could receive adjuvant chemotherapy in most cases especially when the response was poor (data not shown). Long-term follow-up of the two patient groups is warranted.Considering pCR and/or clinical response is not a reliable surrogate endpoint for survival, and the most important role of neoadjuvant systemic therapy in ER-positive/HER2-negative breast cancer is expanding the pool of potential BCS candidates by downstaging tumours and permitting BCS in patients who would otherwise require mastectomy . In our A potential advantage of neoadjuvant therapy is avoidance of axillary lymph node dissection in patients who have had negative conversion of tumour-positive lymph nodes. NCT downstages axillary nodes in 20 to 40% of patients, and these rates are even higher (> 50%) in HER2-positive patients given anti-HER2 therapy –21. Two Most NET studies in breast cancer have focused on post-menopausal women , 25, 26.The optimal duration of NET is not well defined. Most previous NET studies applied from 3 to 6 months of therapy. In a study by Llombart-Cussac et al. , 37% of For ER-positive/HER2-negative subtype breast cancer, objective response determination is an issue. pCR, which is the only definite response criteria in neoadjuvant therapy, is highly uncommon; furthermore, it is not a surrogate endpoint for survival in this subtype . We evalThere are some limitations in this study. First, the small sample size which was not satisfied with pre-defined number was included. Second, clinical response or pCR is not a predictor of prognosis in ER-positive and Her2-negative subtypes. This data cannot demonstrate the survival benefit of NCT compared with NET. Third, we did not include the arm of aromatase inhibitor as a NET treatment. In a study that compared neoadjuvant GnRH analogue plus tamoxifen and GnRH analogue plus anastrozole in pre-menopausal women, the clinical response was better in the anastrozole group . BecauseAlthough, in our result for the primary endpoint, NET showed a worse clinical response than NCT, NET cannot be excluded as a clinical option, because (1) the BCS rate was comparable, (2) no difference was observed in Ki-67 change with the therapies, and (3) the adverse event was much smaller in the NET group. This finding indicates that we can recommend NET in clinical practice in ER-positive/HER2-negative breast cancer with low Ki-67 expression, intermediate/low grade tumour, clinically lymph node-negative patients, and for patients with large tumours where BCS is not feasible or equivocal. It is recommended to perform a multigene assay  prior to the start of NET to confirm whether chemotherapy is needed for the individual patient.In pre-menopausal breast cancer patients, 24 weeks of NCT showed a better clinical response than NET except for in a subgroup with low Ki-67 or low grade cancer. However, the breast conservation rate and the Ki-67 change were not different. There may be an issue concerning accurate size measurements with MRI in both groups. Clinicians should be aware of the potential benefits and disadvantages of both treatments. Use of NET in pre-menopausal women requires further discussion.Additional file 1. Drug administration and Statistics.


Background and objective2DS2-VASc score is a stroke risk stratification tool that is used in patients with atrial fibrillation (AF). Most of its clinical variables have been associated with poor outcomes in patients with infective endocarditis (IE). In this study, we aimed to determine its utility in predicting outcomes in IE patients.The CHAMethods2DS2-VASc score was calculated for each patient. Hierarchical logistic regression was used to estimate the adjusted odds ratio for in-hospital mortality for CHA2DS2-VASc scores from 1 to 9, using a score of 0 as the reference score. All clinical characteristics were defined using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes.We included 35,570 patients with IE from the National Inpatient Sample (NIS), 2009-2012. The CHAResults2DS2-VASc scores were associated with increased mortality, and the scores among the sample ranged from 0 for 8.1% to 8 for 21.7%. In the hierarchical logistic regression, after adjusting for age, sex, and relevant comorbidities, as the score increased, so did the odds for overall mortality.The mean age of the sample was 57.81 ±14 years. Higher CHAConclusion2DS2-VASc score may serve as a risk assessment tool with which to predict outcomes. Further studies are needed to replicate these findings.In patients with IE, the CHA Infective endocarditis (IE) is a life-threatening infection of the valvular or paravalvular heart structures; it has an incidence rate of approximately 100 cases per one million patient-years . Althoug2DS2-VASc score was created to predict stroke risks in patients with atrial fibrillation (AF) [2DS2-VASc score was able to predict ischemic strokes and transient ischemic attacks in patients with or without AF [2DS2-VASc score in predicting cardiovascular events and long-term outcomes in patients with Takotsubo cardiomyopathy [The CHAion (AF) ,5. Whilethout AF . In anotthout AF . More remyopathy .2DS2-VASc scoring system incorporates a history of congestive heart failure, hypertension, diabetes, prior stroke, vascular disease, patient age, and sex [2DS2-VASc score and in-hospital mortality among IE patients.The CHA and sex . Some of and sex . Further and sex ,10-12. IStudy designThis was a cross-sectional study. The data related to the study cohort were collected from the National Inpatient Sample (NIS) database, 2009-2012, a subset of the Healthcare Cost and Utilization Project (HCUP) sponsored by the Agency for Healthcare Research and Quality (AHRQ). NIS is the largest all-payer inpatient database in the US. It contains a 20% stratified sample of all discharges from US nonfederal, short-term general hospitals, subspecialty hospitals, and public hospitals. It is stratified based on the number of beds, ownership, hospital teaching status, US region, and state. Stratified random sampling ensures that the database is representative of the US population and accounts for 90% of all hospitalizations in the US after applying appropriate weights. The NIS includes information on demographic characteristics, hospital characteristics, up to 25 diagnostic and procedure codes based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, and outcomes based on patient discharge records. Each record represents a single hospitalization, and thus, multiple records may exist for an individual with recurrent hospitalizations. The details regarding the NIS are freely available online.Study population, variables, and outcomes2DS2-VASc score was calculated for each patient using the following variables: a history of congestive heart failure, hypertension, diabetes, prior stroke, vascular disease, age , and sex . A history of congestive heart failure, hypertension, diabetes, prior stroke, and vascular disease were all identified in any of the 25 available diagnosis codes in the NIS using their respective ICD-9 codes. In addition, NIS variables were used to identify patients’ demographic characteristics, such as age and gender. Other variables that could impact study outcomes, such as a history of endocarditis, hemodialysis, and valve replacement, were also included . The CHAStatistical analysis2DS2-VASc score of 0 was used as the reference score. A p-value of <0.05 was considered to be statistically significant.IBM SPSS Statistics version 25  was used for the statistical analysis. A hierarchical two-level logistic regression model, with hospital ID as a random effect, was used to evaluate the outcome variables. We quantified the predictive validity of the classification schemes by using a two-level model to test the hypothesis that these classification schemes performed significantly better than chance. A study cohort with a CHA2DS2-VASc score are listed in Table 2DS2-VASc score was associated with poorer outcomes in patients with IE. In-hospital mortality increased from 8.1% for a score of 0 to 21.7% for a score of 8 , while a score of 8  was the least prevalent. The baseline characteristics and comorbidities contributing to the CHA2DS2-VASc score as a risk assessment tool in predicting in-hospital IE outcomes. Our findings demonstrated that CHA2DS2-VASc is associated with in-hospital mortality among IE patients. To our knowledge, this is the first study to evaluate the role of the CHA2DS2-VASc score in IE.In this study, we investigated the utility of the CHAIE is associated with a wide variety of complications involving various organ systems. Cardiac complications range from congestive heart failure to myocardial abscess and valvular perforation . NeuroloCurrent IE management strategies are based on presumed patient risk. Low-risk patients can be safely managed with antibiotics, while early aggressive interventions, such as cardiac surgery, are recommended for those with a high risk of mortality . These i2DS2-VASc score may serve as a risk assessment tool in patients with IE. In our study, patients with a score of 2 or more had mortality rates greater than 10%. In-hospital mortality rates increased as the score increased, from 12% for a score of 2 to 21.7% for a score of 8. The odds of in-hospital mortality doubled at a score of 2. It increased by 20% for a score of 2 as compared to a score of 1, and it further increased by 38% for a score of 3 as compared to a score of 2. This suggests that this model may be used to risk-stratify patients with IE. Patients with high scores  may benefit from early surgery and closer monitoring.A scoring system that leads to adequate patient selection, bedside decision-making, and patient education and provides prognostic information may help decrease IE-associated mortality. There are currently no validated scoring models to predict in-hospital complications or outcomes of IE. Current models have focused on long-term outcomes and complications after cardiac surgery -25. As d2DS2-VASc score. One potential explanation is that a higher level of comorbidity is associated with a higher score. Another plausible explanation is that the scoring system incorporates certain specific disease conditions  that have been associated with poorer outcomes in patients with IE, as we hypothesized. One limitation of using this scoring system would be the absence of important clinical variables, such as echocardiographic features and organisms involved, which have been linked to poor prognosis in patients with IE.Prognosis in IE patients is driven by patient characteristics, the presence or absence of cardiac complications, infecting organisms, and echocardiographic features . PatientOur study has some limitations related to the NIS database. Firstly, the NIS is an administrative database fraught with variations in institutional coding practices; hence, it is susceptible to coding errors. Secondly, we had no data on clinical variables such as echocardiographic features, vegetation size, vital signs, and the organisms involved, all of which have a significant impact on the rates of complications ,26. Also2DS2-VASc score may help with risk-stratifying patients with IE. Further studies are needed to replicate this finding and to investigate how the tool can be implemented in in-patient management and bedside decision-making.In conclusion, the CHA


Standard treatment for localized renal cell carcinoma (RCC) is surgery. Stereotactic radiotherapy given in a few high dose fractions is a promising treatment for this indication and could be an alternative option for patients unsuitable for surgery. Stereotactic MR-guided radiotherapy (MRgRT) is clinically implemented as a new technique for precise treatment delivery of abdominal tumors, like RCC. In this study, we evaluated the clinical impact of stereotactic MRgRT given in five fractions of 8 Gy and routine plan re-optimization for 36 patients with large primary RCCs. Our evaluation showed good oncological results with minimal side-effects. Even in this group with large tumors, daily plan re-optimization was only needed in a minority of patients who can be identified upfront. This is a favorable result since online MRgRT plan adaptation is a time-consuming procedure. In these patients, MRgRT delivery will be faster, and these patients could be candidates for even less fractions per treatment.Novel magnetic-resonance-guided radiotherapy (MRgRT) permits real-time soft-tissue visualization, respiratory-gated delivery with minimal safety margins, and time-consuming daily plan re-optimisation. We report on early clinical outcomes of MRgRT and routine plan re-optimization for large primary renal cell cancer (RCC). Thirty-six patients were treated with MRgRT in 40 Gy/5 fractions. Prior to each fraction, re-contouring of tumor and normal organs on a pretreatment MR-scan allowed daily plan re-optimization. Treatment-induced toxicity and radiological responses were scored, which was followed by an offline analysis to evaluate the need for such daily re-optimization in 180 fractions. Mean age and tumor diameter were 78.1 years and 5.6 cm, respectively. All patients completed MRgRT with an average fraction duration of 45 min. Local control (LC) and overall survival rates at one year were 95.2% and 91.2%. No grade ≥3 toxicity was reported. Plans without re-optimization met institutional radiotherapy constraints in 83.9% of 180 fractions. Thus, daily plan re-optimization was required for only a minority of patients, who can be identified upfront by a higher volume of normal organs receiving 25 Gy in baseline plans. In conclusion, stereotactic MRgRT for large primary RCC showed low toxicity and high LC, while daily plan re-optimization was required only in a minority of patients. A radical or partial nephrectomy is the preferred standard curative treatment for localized renal cell carcinoma (RCC) ,2,3,4. ATechnical challenges in renal SABR include the management of intra-fractional motion, and potential solutions using an internal target volume-approach, fiducial-assisted robotic SABR or abdominal compression  have beeStereotactic MRgRT with routine daily plan adaptation was clinically implemented at our center in 2016 for a variety of clinical indications. The aim of the current paper is to describe our technique, early clinical outcomes, and the role of daily plan adaptation in MRgRT for patients with primary large RCC.n = 36), local recurrences (n = 5), renal metastases from other primary tumors (n = 3), or a diagnosis of urothelial carcinoma (n = 7). This analysis is restricted to the remaining 36 patients who were treated for primary RCC.Data from all patients treated with MRgRT on the MRIdian-system  at the Amsterdam University Medical Centers are collected within a prospective institutional review board approved database. Between May 2016 and February 2020, a total of 51 patients were treated for a primary RCC , and subsequently re-optimized using the target and OAR optimization objectives of the baseline plan (“re-optimized plan”). Plan re-optimization prioritizes avoiding high doses to OARs, even when this is at the cost of decreased PTV coverage. Both the predicted and re-optimized plans are reviewed, and the re-optimized plan is selected for the actual delivery.MRgRT delivery is performed using respiratory gating during subsequent breath-hold periods in shallow inspiration. The tracking structure for gating is either the primary tumor, or the kidney itself on a single sagittal plane , dependiBaseline patient and tumor characteristics and follow-up data including LC, renal function, and toxicity were collected. Acute and late toxicity was scored using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Follow-up imaging was assessed by a CT-scan or ultrasound, and the tumor response was classified according to RECIST 1.1. criteria.38Gy of the GTV ≥ 90%, and V33Gy ≤ 1 cc for stomach, duodenum, and bowel. Re-optimization was defined as “needed” when the predicted plan violated the above-mentioned GTV and/or OAR constraints, which was subsequently corrected by re-optimization. In contrast, plan re-optimization was defined as “redundant” when predicted plans already complied with the planning objectives. In addition, the value of plan re-optimization was analyzed on a patient level by studying the number of fractions per patient that were considered suboptimal.An offline analysis was performed to evaluate the need for daily plan re-optimization in MRgRT for RCC in a total of 180 fractions. For this purpose, predicted and re-optimized plans were analyzed for adherence with planning target objectives and OAR constraints, i.e., a Vt-test. Local, regional, distant disease control and overall survival (OS) were estimated using the Kaplan-Meier method. OS was calculated as the time between the first fraction of MRgRT and the date of the last follow-up. LC was calculated as the time between the first fraction of MRgRT and the date of last imaging. Statistical analysis used for plan comparisons was performed using the Wilcoxon Signed-Rank test. A p-value of < 0.05 was considered to be statistically significant. Decision tree analysis  was used to explore predictive pretreatment characteristics and most significant cut-off values to identify patients for whom daily re-optimization was needed. Baseline volumetric, geometric, and dosimetric parameters, i.e., GTV size (cc), laterality , location , V33Gy, V30Gy, V25Gy, and V20Gy for each OAR structure separately or combined in one structure were used as input variables. The qualitative re-optimization benefit variable (“redundant” or “needed”) was selected as the target variable for decision tree analysis. The significance level for node splitting was set at p < 0.05. Stopping parameters to prevent over-fitting were applied by setting the minimum number of records in a leaf to be at least 10% of the data set. The Statistical Package for the Social Sciences (SPSS) version 26  was used to perform all statistical analyses.Descriptive statistics were used for baseline patient and tumor characteristics. The change in renal function (eGFR) from baseline versus post-treatment at the latest available time point in follow-up was evaluated using the paired sampled n = 9), which is unsuitable for other ablative therapies due to tumor size (n = 10) or location (n = 5), patient preference (n = 5), co-existing second malignancy (n = 3), use of anti-coagulants (n = 2), and chronic stage ≥IV kidney disease (n = 2). Baseline patient characteristics are summarized in n = 14). Other patients with histology included Fuhrman grade 1 (n = 1), Fuhrman grade 3 (n = 1), a RCC with sarcomatoid features (n = 1), and a chromophobe tumor (n = 1). In two patients, no grading was available because pathologic confirmation was obtained from systemic metastases. All patients were able to complete adaptive MRgRT with an average time per fraction of 45 min. An overview of the average duration of the different components of adaptive MRgRT for RCC is shown in All 36 patients were referred for SABR after discussion in a multidisciplinary tumor board, and reasons for referral included a high surgical risk due to comorbidity  mL/min/1.73 m2, which indicates a decrease of 6.0 mL/min/1.73 m2. No patient in this cohort required dialysis during follow-up.The median follow-up was 16.4 months. Overall survival was 91.2% at one year , LC was 38Gy of 98.8% and 99.1%, respectively, and mean V33Gy of 0 cc for both stomach, duodenum, and bowel. In the other 29 fractions, predicted plans were suboptimal with insufficient GTV coverage in two out of 180 fractions (1.1%) exceeding OAR constraints in 25 fractions (13.9%), and both insufficient GTV coverage and exceeded OAR constraints in another two fractions (1.1%). There was no significant difference in suboptimal predicted plans for left-sided or right-sided RCC (p = 0.56). For these suboptimal plans, on-couch re-optimization corrected the GTV V38Gy from a mean of 88.7% (predicted) to 97.4% (re-optimized). Similarly, re-optimization corrected OAR V33Gy ≤ 1 cc violations from on average V33Gy of 4.1 (predicted plans) to 0.3 cc (re-optimized plans). Analysis on a patient basis showed that the 29 insufficient predicted fractions were distributed among 11 patients . However, three or more suboptimal fractions were seen in only five patients (13.9%).In 151 out of 180 fractions (83.9%), the predicted plans (without re-optimization) met all institutional target and OAR constraints. In these fractions, predicted and re-optimized plans were of similar quality with a mean GTV V25Gy  as the most significant predictor variable for daily adaptive planning needs with 0.5 cc as an optimal cut-off value (p < 0.001). In all cases with a baseline OAR V25Gy of ≤ 0.5 cc, plan adaptation was redundant as the predicted plans already complied with institutional constraints. In patients with baseline OAR V25Gy of more than 0.5 cc, plan re-optimization was needed in 32.2% of fractions in order to fulfill the preset target coverage and OAR constraints (95%) and OAR (V33Gy) stratified for split group 1 and 2  mL/min/1.73 m2 that was described in previous SABR studies [MRgRT with daily plan re-optimization was feasible with an average fraction duration of 45 min, even in poorer condition patients with multiple co-existing diseases. Despite this prolonged treatment duration, all patients were able to complete treatment, which indicates good tolerability. Our fractionation scheme of 40 Gy in five fractions is commonly used and seems safe without severe toxicity. With a mean interval of well over one year, the mean decline in eGFR in our study was only 6.0 (SD ± 9.8) mL/min/1.73 m studies ,28. This25Gy of the combined OAR of less than 0.5 cc in the baseline plan. It is, however, unlikely that an isolated single fraction violating high OAR dose or target constraints will be clinically relevant, and three out of five insufficient predicted plans were seen in only 14% of patients. Performing MRgRT without plan re-optimization indicates that the re-contouring, plan adaptation, and plan quality assurance phases can be omitted, which would enable respiratory-gated MRgRT fractions to be completed in 30 min. Furthermore, when plan adaptation is redundant, this indicates that the presence of the radiation oncologist at the MR Linac is not necessary. As a result of our analysis, we are currently introducing the found V25Gy selection criterion in clinical practice.MRgRT also offers the advantage of using plan re-optimization for each delivered fraction at the cost of additional time. Our offline analysis showed that daily plan re-optimization was required in only 16% of fractions in which the predicted plan failed to meet the predetermined high-dose OAR constraints or target coverage objectives. Decision tree analysis showed that patients for whom daily plan re-optimization is not required can be identified upfront on the basis of a VThe main limitation of our study is the relative short and unstructured patient follow-up. The limited number of RCC patients reflects the limited role of SABR in current international treatment guidelines, as only patients unsuitable for or refusing other local treatments are referred for curative radiation therapy. Another limitation includes the absence of pathology in half of our patients. Incomplete pathology confirmation is partly inherent to our patient population with generally frail elderly patients, which is unsuitable for other treatment modalities. Moreover, in a number of patients, a diagnostic biopsy was considered contra-indicated because of anticoagulant use or the anatomical location of the tumor. All patients had been discussed in a multidisciplinary tumor board with access to all available diagnostic imaging. Contrast enhanced multi-phasic CT has a high sensitivity and specificity for characterization and detection of RCC ,29 and tPrior to the MRgRT era, the need for radiologists to implant fiducial markers has also been an obstacle for referral for SABR. Our data show that MRgRT can be a valid alternative in patients unsuitable for the more commonly used local treatments, because of patient vitality or tumor size. The only contra-indication for MRgRT is having MR-incompatible devices. The main advantage of MRgRT is that it is an outpatient, non-invasive treatment for which not even the placement of fiducial markers is necessary. Whether MRgRT can also be considered as an alternative to partial nephrectomy or cryotherapy needs to be addressed in a prospective randomized study, which should also evaluate quality of life and cost-effectiveness. With regard to the favorable outcome in the data on SABR literature as well as the current analysis on MRgRT, a more prominent role of SABR in the treatment guidelines for RCC appears warranted.25Gy of ≤ 0.5 cc in the baseline plans. This is a favorable result since online MRgRT plan adaptation is a time-consuming procedure. In this group of patients, MRgRT delivery will be faster, and these patients could be candidates for further hypofractionation [In conclusion, hypo-fractionated MRgRT for large RCC resulted in high LC and very low toxicity rates. Gated treatment without the need for anesthesia or fiducials appeared well tolerated. Even in this group with large RCCs, daily plan re-optimization was not needed for the majority of patients, who can be identified upfront by a combined OAR Vionation .